Advanced-Stage Non-Driver NSCLC: Frontline Options

Benjamin P. Levy, MD:The frontline options for an adenocarcinoma patient without a driver mutation, that’s PD-L1—negative, is evolving rapidly. I want to say if we had this conversation 6 months ago, or 12 months ago, I would have said chemotherapy with or without bevacizumab. And the chemotherapy backbones that people use are different. Some people use carboplatin/paclitaxel/bevacizumab. I tend to favor carboplatin/pemetrexed/bevacizumab based on its better tolerability. But the world is changing in a frontline arena. We now have immunotherapy that can be added to chemotherapy, so we have data coming from KEYNOTE-189 showing carboplatin/pemetrexed/pembrolizumab may be an approved regimen. Then finally we have the 4-drug regimen from IMpower150: carboplatin/paclitaxel/bevacizumab/atezolizumab. I think this is where treatment decisions really have to be individualized.

For a never-smoking patient with a PD-L1 less than 0%, it would be unlikely for me to use immunotherapy. We’ll have data very soon to understand what the benefit is of pembrolizumab in PD-L1 less than 50% when added to chemotherapy. But for a never-smoking patient in whom I’m trying to elicit a response, I would generally use a platinum doublet with bevacizumab. We want to get a response, we want to decrease the tumor burden, and we want to lessen symptoms. In a never-smoker, I’m just not confident that immunotherapy would do that with a PD-L1 of 0%. And so, this is a case where I would consider using the triplet of carboplatin/pemetrexed/bevacizumab or, if you wanted to go strictly by the ECOG 4599 data, carboplatin/paclitaxel/bevacizumab.

There’s lots of rationale to adding bevacizumab for this patient who has a low PD-L1, who’s a never-smoker, and who’s symptomatic. We know that from the ECOG 4599 study, when we added bevacizumab to cytotoxic chemotherapy, it improved response rate, improved progression-free survival, and included overall survival. And in a very young fit patient like this, bevacizumab would be routinely incorporated in my platinum doublet. Bevacizumab is not for all patients, and I don’t add it to every patient I see. I don’t add it to a platinum doublet, but for patients who are young, who are fit, who are never-smokers, who lack a driver mutation, and who are PD-L1 low, until I see more data from KEYNOTE-189—and we’ll have that very soon—I would favor using bevacizumab in combination with carboplatin and pemetrexed.

Age and performance status factor in for me when I’m thinking about using bevacizumab or any antiangiogenic strategy. I generally use this regimen in younger patients. I think the benefit is there in younger patients. And then performance status, I think, is important. This drug, while well tolerated, can add toxicities. So, patients with a performance status of 2, those are patients where maybe I wouldn’t use 3 drugs. Rather I would use 2, just a platinum doublet and carboplatin and pemetrexed. But for patients who are younger, who are fit, I think this is the right scenario to consider the use of bevacizumab in combination with a platinum doublet.

Transcript edited for clarity.

• A 55-year old female presented with chronic cough and 10-lb weight loss
• PMH: never smoker; no family history of cancer; no known exposure to chemicals or asbestos
• Chest x-ray showed a 5.0-cm lesion in the left lower lobe with bulky lymphadenopathy
• Chest CT scan confirmed the presence of a lung mass and enlargement of the right hilar lymph node and bilateral mediastinal lymph nodes
• EUS-guided biopsy was performed
• Pathology revealed adenocarcinoma
• Molecular testing:
  • FISH: negative for ALK translocation
  • NGS: negative for EGFR, ROS1, RET, BRAF, KRAS
  • IHC: PD-L1 expression in 0% of cells
• PET/CT imaging showed 18F-FDG uptake in the lung mass, right hilar lymph node, mediastinum, and left adrenal gland
• MRI of the brain was normal
• ECOG PS, 0
• The patient was started on therapy with carboplatin/pemetrexed and bevacizumab
• The regimen was well tolerated
• After 6 cycles, the patient had a good response
• She was continued on bevacizumab
• After 9 months on therapy, the patient developed cough and weight loss
• Follow-up imaging revealed multiple new lesions in the left adrenal gland and new liver metastases
• Patient was started on atezolizumab, planned for 12 months